Abstract
Introduction: Cervical cancer is the third most common tumor among women. Surgery, radiotherapy, and chemotherapy are common treatments, however high stage tumors have frequently poor prognosis. Nowadays, the epigenetic reversion introduced as an efficient strategy of treatment of cervical cancer. In the process, inhibitors of DNA methyltransferase (DNMT) induce re-expression of tumor suppressor genes. Among these inhibitors, disulfiram (DSF) has been suggested as non-nucleoside analogous. In this research, we evaluated the epigenetic effect of DSF on demethylation of the tumor suppressor gene, RASSF1A, in Hela cell line. Materials and methods: Hela cells were cultured and treated with different doses from 2.5 to 37.5µM during 24, 48 and 72 hours. MTT assay was carried out to find half maximal inhibitory concentration (IC50). The methylation specific PCR (MSP) assay was applied to evaluate methylation pattern. Results: The IC50 of DSF was determined at the 2.5, 12.5, and 15µM after72 hours. The MSP results showed partial demethylation at mentioned concentrations after 72h but unmethylated band was not observed after 24h. Conclusion: Our findings indicated that, IC50 of DSF exerted a biphasic effect in Hela cell line and at least 72 hours treatment is needed for the epigenetic reversion of DSF on RASSF1Ain Hela cell line.
Highlights
Cervical cancer is the third most common tumor among women
DNA hypermethylation in CPG Islands of promoter region in tumor suppressor genes induces gene silencing without alteration in DNA sequences which are inherited from one generation to the [7,8]
The cytosine analogous DNA methyl-transferase inhibitor (DNMTi) such as 5Aza-CdR which was approved by FDA and used as combined cancer therapy in lymphoma and hematopoietic cancer is toxic [13]
Summary
Cervical cancer is the third most common tumor among women. Surgery, radiotherapy, and chemotherapy are common treatments, high stage tumors have frequently poor prognosis. Inhibitors of DNA methyltransferase (DNMT) induce re-expression of tumor suppressor genes. Among these inhibitors, disulfiram (DSF) has been suggested as non-nucleoside analogous. We evaluated the epigenetic effect of DSF on demethylation of the tumor suppressor gene, RASSF1A, in Hela cell line. The epigenetic events are reversible, for instance using DNA methyl-transferase inhibitor (DNMTi) drugs are recommended to revise abnormal methylation in promoter region of tumor suppressor genes[11]. For more than 50 years, DSF has been advised for alcohol abuse, but, recent studies have demonstrated the antineoplastic effect of this drug on different tumors and cancer cell lines such as Melanoma, glioma, lung carcinoma, and leukemia[15]. The exact antineoplastic effect of DSF is not clear, so in this study we investigated the epigenetic effect of DSF on re-expression of RASFF1A on cervical cancer cell line
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